In a challenge to current thinking about cognitive impairment, this book
explores what it means to treat people with intellectual disabilities in an ethical
manner. Reassessing philosophical views of ...intellectual disability, Licia Carlson
shows how we can affirm the dignity and worth of intellectually disabled people
first by ending comparisons to nonhuman animals and then by confronting our fears
and discomforts. Carlson presents the complex history of ideas about cognitive
disability, the treatment of intellectually disabled people, and social and cultural
reactions to them. Sensitive and clearly argued, this book offers new insights on
recent trends in disability studies and philosophy.
Fragile X is the most common known inherited cause of intellectual disability and autism, and it typically results from transcriptional silencing of FMR1 and loss of the encoded protein, FMRP ...(fragile X mental retardation protein). FMRP is an mRNA-binding protein that functions at many synapses to inhibit local translation stimulated by metabotropic glutamate receptors (mGluRs) 1 and 5. Recent studies on the biology of FMRP and the signaling pathways downstream of mGluR1/5 have yielded deeper insight into how synaptic protein synthesis and plasticity are regulated by experience. This new knowledge has also suggested ways that altered signaling and synaptic function can be corrected in fragile X, and human clinical trials based on this information are under way.
The aim of the study was to redefine the phenotype of Allan–Herndon–Dudley syndrome (AHDS), which is caused by mutations in the SLC16A2 gene that encodes the brain transporter of thyroid hormones. ...Clinical phenotypes, brain imaging, thyroid hormone profiles, and genetic data were compared to the existing literature. Twenty‐four males aged 11 months to 29 years had a mutation in SLC16A2, including 12 novel mutations and five previously described mutations. Sixteen patients presented with profound developmental delay, three had severe intellectual disability with poor language and walking with an aid, four had moderate intellectual disability with language and walking abilities, and one had mild intellectual disability with hypotonia. Overall, eight had learned to walk, all had hypotonia, 17 had spasticity, 18 had dystonia, 12 had choreoathetosis, 19 had hypomyelination, and 10 had brain atrophy. Kyphoscoliosis (n=12), seizures (n=7), and pneumopathies (n=5) were the most severe complications. This study extends the phenotypic spectrum of AHDS to a mild intellectual disability with hypotonia. Developmental delay, hypotonia, hypomyelination, and thyroid hormone profile help to diagnose patients. Clinical course depends on initial severity, with stable acquisition after infancy; this may be adversely affected by neuro‐orthopaedic, pulmonary, and epileptic complications.
What this paper adds
Mild intellectual disability is associated with SLC16A2 mutations.
A thyroid hormone profile with a free T3/T4 ratio higher than 0.75 can help diagnose patients.
Patients with SLC16A2 mutations present a broad spectrum of neurological phenotypes that are also observed in other hypomyelinating disorders.
Axial hypotonia is a consistent feature of Allan–Herndon–Dudley syndrome and leads to specific complications.
What this paper adds
Mild intellectual disability is associated with SLC16A2 mutations.
A thyroid hormone profile with a free T3/T4 ratio higher than 0.75 can help diagnose patients.
Patients with SLC16A2 mutations present a broad spectrum of neurological phenotypes that are also observed in other hypomyelinating disorders.
Axial hypotonia is a consistent feature of Allan–Herndon–Dudley syndrome and leads to specific complications.
Building on work in feminist studies, queer studies and critical race theory, this volume challenges the universality of propositions about human nature, by questioning the boundaries between ...predominant neurotypes and ‘others’, including dyslexics, autistics and ADHDers. This is the first work of its kind to bring cutting-edge research across disciplines to the concept of neurodiversity. It offers in-depth explorations of the themes of cure/prevention/eugenics; neurodivergent wellbeing; cross-neurotype communication; neurodiversity at work; and challenging brain-bound cognition. It analyses the role of neuro-normativity in theorising agency, and a proposal for a new alliance between the Hearing Voices Movement and neurodiversity. In doing so, we contribute to a cultural imperative to redefine what it means to be human. To this end, we propose a new field of enquiry that finds ways to support the inclusion of neurodivergent perspectives in knowledge production, and which questions the theoretical and mythological assumptions that produce the idea of the neurotypical. Working at the crossroads between sociology, critical psychology, medical humanities, critical disability studies, and critical autism studies, and sharing theoretical ground with critical race studies and critical queer studies, the proposed new field – neurodiversity studies – will be of interest to people working in all these areas.
Disorders of creatine transport and metabolism Longo, Nicola; Ardon, Orly; Vanzo, Rena ...
American journal of medical genetics. Part C, Seminars in medical genetics,
15 February 2011, Volume:
157C, Issue:
1
Journal Article
Identifying causative variants in cis-regulatory elements (CRE) in neurodevelopmental disorders has proven challenging. We have used in vivo functional analyses to categorize rigorously filtered CRE ...variants in a clinical cohort that is plausibly enriched for causative CRE mutations: 48 unrelated males with a family history consistent with X-linked intellectual disability (XLID) in whom no detectable cause could be identified in the coding regions of the X chromosome (chrX). Targeted sequencing of all chrX CRE identified six rare variants in five affected individuals that altered conserved bases in CRE targeting known XLID genes and segregated appropriately in families. Two of these variants, FMR1CRE and TENM1CRE, showed consistent site- and stage-specific differences of enhancer function in the developing zebrafish brain using dual-color fluorescent reporter assay. Mouse models were created for both variants. In male mice Fmr1CRE induced alterations in neurodevelopmental Fmr1 expression, olfactory behavior and neurophysiological indicators of FMRP function. The absence of another likely causative variant on whole genome sequencing further supported FMR1CRE as the likely basis of the XLID in this family. Tenm1CRE mice showed no phenotypic anomalies. Following the release of gnomAD 2.1, reanalysis showed that TENM1CRE exceeded the maximum plausible population frequency of a XLID causative allele. Assigning causative status to any ultra-rare CRE variant remains problematic and requires disease-relevant in vivo functional data from multiple sources. The sequential and bespoke nature of such analyses renders them time-consuming and challenging to scale for routine clinical use.
Creatine is physiologically provided equally by diet and by endogenous synthesis from arginine and glycine with successive involvements of arginine glycine amidinotransferase AGAT and ...guanidinoacetate methyl transferase GAMT. A specific plasma membrane transporter, creatine transporter CRTR (SLC6A8), further enables cells to incorporate creatine and through uptake of its precursor, guanidinoacetate, also directly contributes to creatine biosynthesis. Breakthrough in the role of creatine has arisen from studies on creatine deficiency disorders. Primary creatine disorders are inherited as autosomal recessive (mutations affecting GATM for glycine-amidinotransferase, mitochondrial) and GAMT genes) or X-linked (SLC6A8 gene) traits. They have highlighted the role of creatine in brain functions altered in patients (global developmental delay, intellectual disability, behavioral disorders). Creatine modulates GABAergic and glutamatergic cerebral pathways, presynaptic CRTR (SLC6A8) ensuring re-uptake of synaptic creatine. Secondary creatine disorders, addressing other genes, have stressed the extraordinary imbrication of creatine metabolism with many other cellular pathways. This high dependence on multiple pathways supports creatine as a cellular sensor, to cell methylation and energy status. Creatine biosynthesis consumes 40% of methyl groups produced as S-adenosylmethionine, and creatine uptake is controlled by AMP activated protein kinase, a ubiquitous sensor of energy depletion. Today, creatine is considered as a potential sensor of cell methylation and energy status, a neurotransmitter influencing key (GABAergic and glutamatergic) CNS neurotransmission, therapeutic agent with anaplerotic properties (towards creatine kinases creatine–creatine phosphate cycle and creatine neurotransmission), energetic and antioxidant compound (benefits in degenerative diseases through protection against energy depletion and oxidant species) with osmolyte behavior (retention of water by muscle). This review encompasses all these aspects by providing an illustrated metabolic account for brain and body creatine in health and disease, an algorithm to diagnose metabolic and gene bases of primary and secondary creatine deficiencies, and a metabolic exploration by 1H-MRS assessment of cerebral creatine levels and response to therapeutic measures.
•Primary creatine disorders highlight a role of creatine in brain physiology.•SLC6A8 takes part in creatine transport and re-uptake but also in biosynthesis.•Secondary creatine defects stress dependence of creatine metabolism on many pathways.•The high dependence on multiple metabolic pathways supports creatine as a cell sensor.•Creatine is a potential sensor of cell methylation and energy status.
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder caused by a limited expansion of CGG repeats in the 5′ UTR of FMR1. Two mechanisms are proposed to cause FXTAS: RNA ...gain-of-function, where CGG RNA sequesters specific proteins, and translation of CGG repeats into a polyglycine-containing protein, FMRpolyG. Here we developed transgenic mice expressing CGG repeat RNA with or without FMRpolyG. Expression of FMRpolyG is pathogenic, while the sole expression of CGG RNA is not. FMRpolyG interacts with the nuclear lamina protein LAP2β and disorganizes the nuclear lamina architecture in neurons differentiated from FXTAS iPS cells. Finally, expression of LAP2β rescues neuronal death induced by FMRpolyG. Overall, these results suggest that translation of expanded CGG repeats into FMRpolyG alters nuclear lamina architecture and drives pathogenesis in FXTAS.
•CGG repeats in the 5′ UTR of FMR1 are translated through initiation to an ACG codon•Translation of CGG repeats in the polyglycine protein, FMRpolyG, is toxic in mice•FMRpolyG binds and disrupts protein of the nuclear lamina
Sellier et al. show that translation of expanded CGG repeats located in the 5′ UTR of the FMR1 gene require an upstream ACG near-cognate initiation codon. Translation of CGG repeats into a short polyglycine-containing protein, FMRpolyG, is pathogenic in mouse models.
The Fragile X Mental Retardation Protein (FMRP) is an RNA-binding protein essential to the regulation of local translation at synapses. In the mammalian brain, synapses are constantly formed and ...eliminated throughout development to achieve functional neuronal networks. At the molecular level, thousands of proteins cooperate to accomplish efficient neuronal communication. Therefore, synaptic protein levels and their functional interactions need to be tightly regulated. FMRP generally acts as a translational repressor of its mRNA targets. FMRP is the target of several post-translational modifications (PTMs) that dynamically regulate its function. Here we provide an overview of the PTMs controlling the FMRP function and discuss how their spatiotemporal interplay contributes to the physiological regulation of FMRP. Importantly, FMRP loss-of-function leads to Fragile X syndrome (FXS), a rare genetic developmental condition causing a range of neurological alterations including intellectual disability (ID), learning and memory impairments, autistic-like features and seizures. Here, we also explore the possibility that recently reported missense mutations in the FMR1 gene disrupt the PTM homoeostasis of FMRP, thus participating in the aetiology of FXS. This suggests that the pharmacological targeting of PTMs may be a promising strategy to develop innovative therapies for patients carrying such missense mutations.
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